<b>Bijsluiter</b>. De hyperlink naar het originele document werkt niet meer. Daarom laat Woogle de tekst zien die in dat document stond. Deze tekst kan vreemde foutieve woorden of zinnen bevatten en de opmaak kan verdwenen of veranderd zijn. Dit komt door het zwartlakken van vertrouwelijke informatie of doordat de tekst niet digitaal beschikbaar was en dus ingescand en vervolgens via OCR weer ingelezen is. Voor het originele document, neem contact op met de Woo-contactpersoon van het bestuursorgaan.<br><br>====================================================================== Pagina 1 ======================================================================

<pre>Epichlorohydrin
(1-chloro-2,3-epoxypropane)
Health based calculated occupational cancer risk values
</pre>

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<pre></pre>

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<pre>Aan de Staatssecretaris van Sociale Zaken en Werkgelegenheid
Onderwerp           : Aanbieding advies
Uw kenmerk          : DGV/BMO-U-932542
Ons kenmerk         : U 1888/AB/jt/459-H31
Bijlagen            :1
Datum               : 6 september 2000
Bij brief van 3 december 1993, nr DGV/BMO-U-932542, verzocht de Staatssecretaris
van Welzijn, Volksgezondheid en Cultuur namens de Minister van Sociale Zaken en
Werkgelegenheid om gezondheidskundige advieswaarden af te leiden ten behoeve van de
bescherming van beroepsmatig aan stoffen blootgestelde personen.
Per 1 januari 1994 heeft mijn voorganger daartoe een commissie ingesteld die de
werkzaamheden voortzet van de Werkgroep van Deskundigen (WGD). De WGD was
een door genoemde minister ingestelde adviescommissie.
Hierbij bied ik u - gehoord de Beraadsgroep Gezondheid en Omgeving - een publicatie
van de commissie aan over epichloorhydrine (1-chloor-2,3-epoxypropaan). Deze publi-
catie heb ik heden ter kennisname aan de Minister van Volksgezondheid Welzijn en
Sport en aan de Minister van Volkshuisvesting Ruimtelijke Ordening en Milieubeheer
gestuurd.
w.g.
prof. dr JJ Sixma
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<pre></pre>

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<pre>Epichlorohydrin
(1-chloro-2,3-epoxypropane)
Health based calculated occupational cancer risk values
Dutch Expert Committee on Occupational Standards,
a committee of the Health Council of the Netherlands
to
the Minister and State Secretary of Social Affairs and Employment
No. 2000/10OSH, The Hague, 6 September 2000
</pre>

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<pre>Preferred citation:
Health Council of the Netherlands: Dutch Expert Committee on Occupational Standards
(DECOS). Epichlorohydrin (1-chloro-2,3-epoxypropane; Health-based calculated occu-
pational cancer risk values. The Hague: Health Council of the Netherlands, 2000; publi-
cation no. 2000/10OSH.
all rights reserved
ISBN: 90-5549-337-6
</pre>

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<pre>    Contents
    Samenvatting 9
    Executive summary 11
1   Scope 13
1.1 Background 13
1.2 Committee and procedure 14
2   Epichlorohydrin (1-chloro-2,3-epoxypropane) 15
2.1 Introduction 15
2.2 Carcinogenicity studies and selection of study
    suitable for risk estimation in the occupational situation 15
2.3 Carcinogenic activity in experimental animals, lifetime low-dose exposure 16
2.4 Health risk to humans 17
2.5 Calculation of the HBC-OCRV 17
2.6 Existing occupational exposure limits 18
    References 21
7   Contents
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<pre>  Annexes 23
A Request for advice 25
B The committee 27
C Comments on the public draft 29
D Animal studies 31
8 Epichlorohydrin (1-chloro-2,3-epoxypropane)
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<pre>  Samenvatting
  Op verzoek van de Minister van Sociale Zaken en Werkgelegenheid schat de Commissie
  WGD van de Gezondheidsraad het extra kankerrisico bij beroepsmatige blootstelling aan
  stoffen die door de Europese Unie of door de Commissie WGD als genotoxisch kank-
  erverwekkend zijn aangemerkt. In dit rapport maakt zij zo’n schatting voor epichloorhy-
  drine. Zij heeft daarbij gebruik gemaakt van de methode die is beschreven in het rapport
  ‘Berekening van het risico op kanker’ (1995/06WGD) (Dec95).
  Naar schatting van de commissie is de extra kans op kanker voor epichloorhydrine:
       4 x 10-5 bij 40 jaar beroepsmatige blootstelling aan 0.19 mg/m3
       4 x 10-3 bij 40 jaar beroepsmatige blootstelling aan 19 mg/m3
9 Samenvatting
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<pre>10 Epichlorohydrin (1-chloro-2,3-epoxypropane)</pre>

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<pre>   Executive summary
   On request of the Minister of Social Affairs and Employment the Dutch Expert Commit-
   tee on Occupational Standards (DECOS), a committee of the Health Council of the
   Netherlands, estimates the additional lifetime cancer risk associated with occupational
   exposure to substances that have been classified by the European Union or the DECOS
   as genotoxic carcinogen. In this report the committee presents such estimates for
   epichlorohydrin. It has used the method described in the report ‘Calculating cancer risks
   due to occupational exposure to genotoxic carcinogens’ (1995/06WGD) (Dec95).
   The committee estimated that the additional lifetime cancer risk for epichlorohydrin
   amounts to:
       4 x 10-5 for 40 years of occupational exposure to 0.19 mg/m3
       4 x 10-3 for 40 years of occupational exposure to 19 mg/m3
11 Executive summary
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<pre>12 Epichlorohydrin (1-chloro-2,3-epoxypropane)</pre>

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<pre>Chapter 1
        Scope
1.1     Background
        In the Netherlands, occupational exposure limits for chemical substances are set using a
        three-step procedure. In the first step, a scientific evaluation of the data on the toxicity of
        the substance is made by the Dutch Expert Committee on Occupational Standards
        (DECOS), a committee of the Health Council of the Netherlands, on request of the Min-
        ister of Social Affairs and Employment (annex A). This evaluation should lead to a
        health-based recommended exposure limit for the concentration of the substance in air.
        Such an exposure limit cannot be derived if the toxic action cannot be evaluated using a
        threshold model, as is the case for substances with genotoxic carcinogenic properties.
             In this case an exposure-response relationship is recommended for use in regulatory
        standard setting, ie. the calculation of so-called health-based calculated occupational
        cancer risk values (HBC-OCRVs). The committee calculates HBC-OCRVs for com-
        pounds which are classified as genotoxic carcinogens by the European Union or by the
        present committee.
             For the establishment of the HBC-OCRV’s the committee generally uses a linear ex-
        trapolation method, as described in the committee’s report ‘Calculating cancer risk due
        to occupational exposure to genotoxic carcinogens’ (1995/06WGD). The linear model to
        calculate occupational cancer risk is used as a default method, unless scientific data
        would indicate that using this model is not appropriate.
             In the next phase of the three-step procedure, the Social and Economic Council ad-
        vises the Minister of Social Affairs and Employment on the feasibility of using the
13      Scope
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<pre>    HBC-OCRVs as regulatory occupational exposure limits. In the final step of the proce-
    dure the Minister sets the official occupational exposure limits.
1.2 Committee and procedure
    The present document contains the derivation of HBC-OCRVs for epichlorohydrin by
    the committee. The members of the committee are listed in Annex B. The first draft of
    this report was prepared by MI Willems, from the TNO Nutrition and Food Research
    Institute in Zeist, by contract with the Ministry of Social Affairs and Employment.
         In 1998, the President of the Health Council released a draft of the report for public
    review. The individuals and organisations that commented on the draft are listed in an-
    nex C. The committee has taken these comments into account in deciding on the final
    version of the report.
14  Epichlorohydrin (1-chloro-2,3-epoxypropane)
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<pre>Chapter 2
        Epichlorohydrin
        (1-chloro-2,3-epoxypropane)
2.1     Introduction
        The carcinogenicity of epichlorohydrin has been evaluated by VROM (Bes84), IARC
        (IARC76; IARC87) and the ACGIH (ACG91). These organisations have concluded that
        there is sufficient evidence for carcinogenicity to animals, but inadequate evidence for
        carcinogenicity to humans. Previously, the Dutch Expert Committee on Occupational
        Standards has concluded that epichlorohydrin is a genotoxic carcinogen (WGD86).
             The present evaluation of the carcinogenicity was based on a review by IARC
        (IARC76, IARC87). In addition, literature was retrieved from online databases Medline,
        Toxline and Cancerlit covering the period 1975 to 1996*.
2.2     Carcinogenicity studies and selection of study suitable for risk estimation
        in the occupational situation
        The available epidemiological data do not allow quantitative risk assessment for
        epichlorohydrin.
        Table 1 (Annex D) summarizes the main carcinogenicity studies with experimental ani-
        mals with test conditions and results. Epichlorohydrin has been tested in rats by oral ad-
        ministration (via gavage or drinking water), inducing papillomas and carcinomas of the
*       After completion of the report, IARC concluded in 1999 that epichlorohydrin is a IARC group 2A compound
        (IARC99).
15      Epichlorohydrin (1-chloro-2,3-epoxypropane)
</pre>

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<pre>    forestomach and by inhalation, inducing papillomas and squamous cell carcinomas of
    the nasal cavity. Epichlorohydrin gave negative results after continuous skin painting,
    but was weakly active as an initiator on mouse skin using phorbolmyristate as promotor
    (Duu74, Bes84). Subcutaneous injection of epichlorohydrin in mice resulted in sarcomas
    on the injection site. Epichlorohydrin was negative in the mouse-lung tumour bioassay
    upon intraperitoneal injection (Duu74, Bes84). Rat inhalation experiments published by
    Laskin et al. (Las80) are used to calculate the potential risk of cancer at the workplace.
    Laskin et al (Las80) exposed male rats either to (I) atmospheres containing 0 and 100*
    ppm in air for a period of 30 days or to (II) atmospheres containing 0, 10 and 30 ppm
    for lifetime. The short-term 30 day-exposure regimen with 100 ppm epichlorohydrin
    produced malignant squamous cell carcinomas of the nasal cavity in 15 of 140 rats and
    respiratory tract papillomas in 3 rats. Among 100 rats, lifetime exposure to 30 ppm
    yielded 1 malignant squamous carcinoma of the nasal cavity plus 1 nasal papilloma. No
    nasal or respiratory tract tumours were produced by lifetime exposure of 100 rats to 10
    ppm or in 100 air-treated and 50 untreated controls.
2.3 Carcinogenic activity in experimental animals, lifetime low-dose exposure
    To calculate the carcinogenic activity expressed as the incidence per mg
    epichlorohydrin/m3, the number of animals bearing tumours of interest i.e. squamous cell
    carcinomas in the nasal cavity, and nasal and bronchial papilloma in the 30 ppm group
    in the study of Laskin et al. was used as starting point (Las80). The committee is of the
    opinion that the available data do not indicate that the use of the linear model is not ap-
    propriate.
         The committee is aware of the fact that after lifetime exposure to 30 ppm, only 2 out
    of 100 animals developed a treatment-related tumour, ie one squamus cell carcinoma and
    one pappiloma. However, these results were confirmed in another study of Laskin et al
    in which after exposure to 100 ppm epichlorohydrin for only 30 days, squamous cell
    carcinomas in the nasal cavity were found in 15/140 animals, nasal papilloma in 2/140
    animals and bronchial papilloma in 1/140 animals. Because of the short exposure period
    (30 day), the committee did not found this latter study useful for the linear extrapolation
    to lifetime risk.
    The incidence of tumour bearing animals per mg/m3 (lifespan conditions assuming a lin-
    ear dose-response relationship), Iconcentration, is calculated as follows:
*   1 ppm = 3.78 mg/m3
16  Epichlorohydrin (1-chloro-2,3-epoxypropane)
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<pre>                                                                                                              =
                                                                     Ie - Ic
         Iconcentration*=      C x (Xpo /L) x (Xpe /L) x exposure hours per day/24 x exposure days per week/7
                         2       0
                             - 100
                        100
                                               = 1.1 × 10 −3
         = 115 x     952
                  ( 1000        952
                         ) x ( 1000 ) x  6
                                        24
                                           x 5
                                             7                [mg/m3]-1
2.4 Health risk to humans
    To estimate the additional lifetime risk of cancer in humans under lifespan conditions on
    the basis of results in animal experiments, it is assumed that no difference exists between
    experimental animals and man with respect to toxicokinetics, mechanism of tumour in-
    duction, target, susceptibility etc, unless specific information is available which justifies
    a different approach. Furthermore, it is assumed that the average man lives 75 years,
    weights 70 kg and is exposed 24 hours per day 7 days/week, 52 weeks per year for life-
    time.
2.5 Calculation of the HBC-OCRV
    To estimate the additional lifetime risk of cancer in humans under workplace exposure
    conditions, it is assumed that the average man lives 75 years, is exposed 8 hours per day,
    five days a week, 48 weeks a year, for 40 years, and inhales 10 m3 per 8 hour-working
    day. Using as starting point the estimated incidence of 1.1 x 10-3 per mg/m3, the addi-
    tional lifetime cancer risk per mg/m3 under occupational exposure conditions, HBC-
    OCRV, amounts to:
         HBC-OCRV = 1.1x10 −3 x 75y x 52w                       x 7d x 18m3 = 2.1x10 −4 [mg/m 3 ] −1
                                                       40y  48w 5d 10m      3
    Based on the HBC-OCRV of 2.1 x 10-4 per mg/m3 the reference additional lifetime can-
    cer risk amounts to:
         4 x 10-5 for 40 years of exposure to 0.19 mg/m3
         4 x 10-3 for 40 years of exposure to 19 mg/m3
*   I =the carcinogenic activity attributable to the exposure to the substance per unit daily dose under lifespan conditions
    assuming a linear dose response relationship
    Ie and Ic = incidence of tumour bearing animals or tumours in exposed and control amnimals, respectively,
    Xpo = exposure period, Xpe = experimental period
    and L = standard lifespan for the animals in question (L rat is assumed to be 1000 days)
17  Epichlorohydrin (1-chloro-2,3-epoxypropane)
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<pre>2.6 Existing occupational exposure limits
    Table 2 summarizes the occupational exposure limits established by the regulatory
    authorities of Germany, Sweden and United Kingdom and by USA-ACGIH. No occupa-
    tional exposure limit has been established in The Netherlands and Germany.
           The lowest occupational exposure limit settled by these countries amounts to 1.9
    mg/m3. In the United Kingdom, it was concluded that considering the carcinogenicity
    data, a threshold could not be identified and that consequently a maximum exposure
    limit (MEL)* (1.9 mg/m3) was appropriate. This concentration is about a factor 10
    lower than the concentration leading to an additional cancer risk of 4 x 10-3 (i.e., 19
    mg/m3) and about a factor 10 higher than the concentration leading to an additional can-
    cer risk of 4 x 10-5 (i.e., 0.19 mg/m3 ).
       Table 2 Occupational exposure limits for epichlorohydrin.
     country                    level                   time relation       annotations              ref.
                                                  3
                                ppm         mg/m
     The Netherlandsa           -           -           -                    -                       ISZW95
                b
     Germany                    (3)         (12)        -                   skin                     DFG96
         c
     UK                         0.5         2           8-h TWA, MEL        new (this indicates a    HSE95
                                1.5         6           STEL                new addition to the
                                                                            list)
     Swedend                    0.5         1.9         8-h TWA             skin, sensitizing        NBO93
                    e
     USA-ACGIH                  0.5         1.9         8-h TWA             skin                     ACG99
     a
           the substance is classified as a carcinogen
     b
           The DFG classifies epichlorohydrin as a category A2 carcinogen; DFG category A carcinogens are
           not assigned a health-based occupational exposure limit, but a so called TRK-value (TRK = Tech-
           nische Richtkonzentrationen), a concentration feasible with currently available technical means.
           TRK-values are given in brackets.
     c
           In the UK, epichlorohydrin has been included in the list of substances defined as carcinogens for
           the purpose of the COSHH regulations 1994. Epichlorohydrin has been assigned the risk phrase
           “R45” (may cause cancer).
     d
           The substance is classified as carcinogenic.
     e
           Limits intended to be changed to 0.5 ppm (1.9 mg/m3). Classified as A3 carcinogen; animal car-
*   In setting a Maximum Exposure Limit (MEL), not only the protection of the health of the employee is considered, also
    socio-economic factors are taken into account. A cost benefit assessment is prepared to assist the considerations of
    these. In practice, MELs have been most often allocated to carcinogens, respiratory sensitizers and to other substances
    for which no threshold level of exposure for the effects can be identified and for which there is no doubt about the seri-
    ousness of the hazard(s) posed by the substance.
18  Epichlorohydrin (1-chloro-2,3-epoxypropane)
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<pre>   For the committee,
   The Hague, 6 September 2000
   dr ASAM van der Burght,               Prof. dr GJ Mulder,
   scientific secretary                  chairman
19 Epichlorohydrin (1-chloro-2,3-epoxypropane)
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<pre>20 Epichlorohydrin (1-chloro-2,3-epoxypropane)</pre>

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<pre>       References
ACG91  American Conference of Governmental Industrial Hygienists (ACGIH). Epichlorohydrin. In: Documenta-
       tion of the Treshold Limit Values and Biological Exposure Indices. 6th ed. Cincinnati OH, USA: ACGIH,
       1991: 550-5.
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). 1999 TLVs(R) and BEIs(R). Guide
       to occupational exposure limits. Cincinnati OH, USA; ACGIH, 1996: 21, 39.
Bes84  Besemer AC, Eggels PG, van Esch GJ, et al. Criteriadocument over epichloorhydrine. The Hague, The
       Netherlands: Distributiecentrum Overheidspublikaties (DOP), 1984; Publikatiereeks Lucht 31.
DEC95  Health Council of the Netherlands: Dutch Expert Committee on Occupational Standards (DECOS). Cal-
       culating cancer risk. The Hague: Health Council of the Netherlands, 1995 publication no 1995/06WGD.
DFG96  Deutsche Forschungsgemeinschaft (DFG): Senatskommission zur Prüfung gesundheitsschädlicher Arbe-
       itsstoffe. MAK- und BAT-Werte-Liste 1996. Maximale Arbeitsplatzkonzentrationen und biologische Ar-
       beitsstofftoleranzwerte. Weinheim, FRG: VCH Verlagsgesellschaft mbH, 1996: 35, 107, 126 (Mitteilung
       32).
Duu74  Duuren BL van, Goldschmidt BM, Katz C, et al. Carcinogenic activity of alkylating agents. J Natl Cancer
       Inst 1974; 53: 695-700.
HSE95  Health and Safety Executive (HSE). Occupational exposure limits 1995. Sudbury (Suffolk), UK: HSE
       Books, 1995: 15, 27, 49 (Guidance note 40/95).
IARC76 International Agency for Research on Cancer (IARC). Cadmium, nickel, some epoxides, miscellaneous
       industrial chemicals and general considerations on volatile anesthetics Lyon, France: IARC, 1976:
       131-7.IARC monographs on the evaluation of carcinogenic risks of chemicals to man, Vol 11.
21     References
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<pre>IARC87 International Agency for Research on Cancer. Overall evaluations of carcinogenicity: an updating of
       IARC monographs Lyon, France: IARC, 1987: 202-3 IARC monographs on the evaluation of carcinogenic
       risks to humans, Volumes 1 to 42; Suppl 7.
IARC99 International Agency for Research on Cancer (IARC). Re-evalualtion of some organic chemicals, hydra-
       zine and hydrogen peroxide (part two). Lyon, France: IARC, 1999: 337-344. In: IARC monographs on the
       evaluation of carcinogenic risk of chemicals to man, Vol 71.
ISZW95 Inspectiedienst van het Ministerie van Sociale Zaken en Werkgelegenheid (I-SZW). De Nationale MAC-
       lijst 1995. The Hague, The Netherlands: Sdu Servicecentrum Uitgeverijen, 1995: 25, 63, 65 (pub no
       P145).
Las80  Laskin S, Sellakumar AR, Kuschner M, et al. Inhalation carcinogenicity of epichlorohydrin in noninbred
       Sprague-Dawley rats. J Natl Cancer Inst 1980; 65: 751-7.
NBO93  National Board of Occupational Safety and Health (NBOSH). Occupational exposure limits. Solna, Swe-
       den: NBOSH, 1993: 32, 76, 77 (Ordinance AFS 1993/9).
Wes85  Wester PW, van der Heijden CA, Bisschop A , et al. Carcinogenicity study with epichlorohydrin (CEP)
       by gavage in rats. Toxicology 1985; 36: 325-39.
WGD86  Werkgroep van Deskundigen (WGD). Rapport inzake grenswaarde epichloorhydrine. The Hague, The
       Netherlands: Sdu Servicecentrum Uitgeverijen, 1986; rep no RA 1/86.
22     Epichlorohydrin (1-chloro-2,3-epoxypropane)
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<pre>A  Request for advice
B  The committee
C  Comments on the public draft
D  Animal studies
   Annexes
23
</pre>

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<pre>24 Epichlorohydrin (1-chloro-2,3-epoxypropane)</pre>

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<pre>Annex A
      Request for advice
      In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State Secretary
      of Welfare, Health and Cultural Affairs, the Minister of Social Affairs and Employment
      wrote:
      Some time ago a policy proposal has been formulated, as part of the simplification of the governmental
      advisory structure, to improve the integration of the development of recommendations for health based
      occupation standards and the development of comparable standards for the general population. A conse-
      quence of this policy proposal is the initiative to transfer the activities of the Dutch Expert Committee on
      Occupational Standards (DECOS) to the Health Council. DECOS has been established by ministerial de-
      cree of 2 June 1976. Its primary task is to recommend health based occupational exposure limits as the
      first step in the process of establishing Maximal Accepted Concentrations (MAC-values) for substances
      at the work place.
      In an addendum, the Minister detailed his request to the Health Council as follows:
      The Health Council should advice the Minister of Social Affairs and Employment on the hygienic aspects
      of his policy to protect workers against exposure to chemicals. Primarily, the Council should report on
      health based recommended exposure limits as a basis for (regulatory) exposure limits for air quality at
      the work place. This implies:
            A scientific evaluation of all relevant data on the health effects of exposure to substances using a
            criteria-document that will be made available to the Health Council as part of a specific request for
            advice. If possible this evaluation should lead to a health based recommended exposure limit, or, in
25    Request for advice
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<pre>       the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a calculated con-
       centration in air corresponding with reference tumour incidences of 10-4 and 10-6 per year.
       The evaluation of documents review the basis of occupational exposure limits that have been re-
       cently established in other countries.
       Recommending classifications for substances as part of the occupational hygiene policy of the gov-
       ernment. In any case this regards the list of carcinogenic substances, for which the classification cri-
       teria of the Directive of the European Communities of 27 June 1967 (67/548/EEG) are used.
       Reporting on other subjects that will be specified at a later date.
   In his letter of 14 December 1993, ref U 6102/WP/MK/459, to the Minister of Social
   Affairs and Employment the President of the Health Council agreed to establish DECOS
   as a Committee of the Health Council. The membership of the Committee is given in an-
   nex B.
26 Epichlorohydrin (1-chloro-2,3-epoxypropane)
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<pre>Annex B
      The Committee
         GJ Mulder, chairman
         professor of toxicology; Leiden University, Leiden
         RB Beems
         toxicologic pathologist; National Institute of Public Health and the Environment,
         Bilthoven
         PJ Borm
         toxicologist; Heinrich Heine Universität Düsseldorf (Germany)
         JJAM Brokamp, advisor
         Social and Economic Council, The Hague
         VJ Feron,
         professor of toxicology; TNO Nutrition and Food Research Institute, Zeist
         DJJ Heederik
         epidemiologist; Wageningen University, Wageningen
         LCMP Hontelez, advisor
         Ministry of Social Affairs and Employment, The Hague
         G de Jong
         occupational physician; Shell International Petroleum Maatschappij, The Hague
         J Molier-Bloot
         occupational physician; BMD Akers bv, Amsterdam
         IM Rietjens
         professor in Biochemical toxicology; Wageningen University, Wageningen.
27    The Committee
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<pre>        H Roelfzema, advisor
        Ministry of Health, Welfare and Sport, Den Haag
        T Smid
        occupational hygienist; KLM Health Safety & Environment, Schiphol and professor
        of working conditions, Free University, Amsterdam
        GMH Swaen
        epidemiologist; Maastricht University, Maastricht
        HG Verschuuren
        toxicologist; DOW Europe, Horgen (Switzerland)
        F de Wit
        occupational physician; Labour Inspectorate, Arnhem
        CA Bouwman, scientific secretary
        Health Council of the Netherlands, Den Haag
        ASAM van der Burght, scientific secretary
        Health Council of the Netherlands, Den Haag
   The first draft of the present advisory report was prepared by M Willems, from the De-
   partment of Occupational Toxicology of the TNO Nutrition and Food Research Insti-
   tute, by contract with the Ministry of Social Affairs and Employment.
   Secretarial assistance: J Toet.
   Lay-out: J van Kan.
28 Epichlorohydrin (1-chloro-2,3-epoxypropane)
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<pre>Annex C
      Comments on the public draft
      A draft of the present report was relased in 1998 for public review. The following or-
      ganisations and persons have commented on the draft document:
          WF ten Berge, DSM, Heerlen
29    Comments on the public draft
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<pre>30 Epichlorohydrin (1-chloro-2,3-epoxypropane)</pre>

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<pre>Annex D
      Animal studies
      See table on the next page.
31    Animal studies
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<pre>Table 1 Carcinogenicity studies with epichlorohydrin.
authors           species           exposure characteristics, dose, experimental   findings                                    remark
                                    period
Konishia          ratb, males, N=16 drinking water at doses of 0, 375, 750 and     forestomach                                 the absolute numbers of
(1980, in                           1500 mg/L. Average total intakes were 0,       hyperplasia : 0%, 78%, 90%, 100%            the “tumours” are not
Bes84)                              8.8, 15.7, and 26.6 mg/rat/day. Exposure-      papillomas : 0%, 0%, 10%, 58%               given.
                                    /experimental period 81 weeks                  carcinomas: 0%, 0%, 10%, 17%                Publication not avail-
                                                                                                                               able
van Esch and      ratb, 50/sex/     gavage, 5 times/week, 104 weeks, 0, 2 and      forestomach lesions at 0, 2, 10 mg/kg       the actual numbers of
        c
Wester (1982      group             10 mg/kg bw/day                                hyperplasia: male, 5/50, 24/40, 6/49        tumour bearing animals
in Bes84)                                                                          female, 3/47, 12/44, 7/39                   are given in Wester et
Wes85                                                                              papilloma: male, 1/50, 6/49, 4/49           al. 1985
                                                                                   female, 2/47, 3/44, 0/39
                                                                                   squamous cell carcinoma:
                                                                                   male, 0/50, 6/49, 35/49
                                                                                   female, 0/47, 2/44, 24/39
                     d
Las80             rat , males       inhalation, 6 hrs/day, 5 days/ week, expo-     nasal cavity 0, 100 ppm                     duration of exposure
exp. 1            (N=140)           sure period 30 days, 0, 100 ppm (385           squamous cell carcinoma: 0/100 (150?),      was less than one-
                                    mg/m3)                                         and 15/140                                  fourth the standard
                                    Xpe = lifetime                                 papillomas: 0/100 (150?), 3/140             lifespan
                     d
exp. 2            rat males         inhalation, 6 hrs/day, 5 days/week, lifetime   nasal cavity 0, 10, 30 ppm
                  (N=100)           exposure (136 weeks), 0, 10, 30 ppm            squamous cell carcinomas: 0/100 (150?),
                                    (0, 38.5, 115.5 mg/m3)                         0/100, 1/100
                                                                                   papilloma: 0/100 (150?), 0/100, 1/100
                         e
Duu74             mouse , females,  skin application, 2 mg 3 times/week,           no tumours were found
                  (N=50)            Xpo = Xpe = 580 days
                  mouse, females,   s.c. injections                                malignant tumours, local                    epichlorohydrin in-
                  (N=50)            dose: 1 mg, once a week                        sarcomas: 1/50, 6/50                        duced sarcomas, but
                                    Xpo = Xpe = 580 days                           adenocarcinomas: 0/50, 1/50                 the P value was border-
                                                                                                                               line (0.05)
                  mouse, females,   ip injections                                  lung papillomas 10/50, 11/30
                  (N=30)            dose: 1 mg, once a week                        local sarcomas 1/50, 0/30
                                    Xpo = Xpe = 580 days
a
      Konishi Y, Kawabata A, Denda A, Ikedam T, Katada H, Maruyama H. Gann 1980; 71: 922-923
b
      strain not give
c
      Esch GJ van, and Wester PW. Unpublished report. National Institute of Public Health and the Environment, Bilthoven, the Netherlands 1982
d
      Sprague-Dawley rat
e
      ICR/HA Swiss mice
32              Epichlorohydrin (1-chloro-2,3-epoxypropane)
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